Current behavioral tests to assess the efficacy of putative novel antidepressants lack the necessary validations to allow them to be a robust and reliable in vivo screen. The overall goal of this Fast Track application is to create a novel screening platform to assess the efficacy of putative antidepressants by combining behavioral and biological phenotyping. This platform, to be developed in collaboration with PsychoGenics, Inc., will include an improved behavioral testing system coupled with specific neurochemical markers that will enable pharmaceutical companies to screen compounds and obtain corresponding behavioral readouts and neurobiological, gene- and protein-expression signatures. Specifically, the results of the behavioral assays in mouse models of depression will be correlated with 3-dimensional volumetric analysis of gene expression within the brains of these animals. Phase I of this Fast Track application will demonstrate the feasibility of high-throughput gene expression mapping for identification of relevant markers that underlie interstrain differences in baseline performance in antidepressant behavioral tests. Milestones for Phase I will include behavioral testing and quantitative neurochemical analysis of interstrain differences in expression of two monoamine transporters that are targets of currently prescribed antidepressants. Phase II of this proposal will correlate specific markers, including gene expression and neurogenesis, with pharmacological differences in interstrain performance on behavioral tests. Milestones for Phase II will include pharmacological and behavioral testing using an improved depression model combining different environmental insults, followed by quantitative analysis of relevant neurochemical markers and neurogenesis. The combination of behavioral and neurochemical readouts will yield a model with high construct, face and predictive validity. Commercial Value: The result of the proposed project will be a well-defined and thoroughly validated mouse model of depression that prospective commercial partners will use to test pharmaceutical interventions and conclusively obtain both behavioral and neuroanatomical results on efficacy and outcome of the intervention. This screening platform will have great impact and value for pharmaceutical research and development.